Lipophilic substances possessing low water solubility often have poor oral bioavailability. These compounds, being hydrophobic by nature, show wetting difficulties and poor dissolution. These properties obviously represent a rate-limiting step in their absorption from solid oral dosage forms and, in turn, cause a subsequent reduction in their bioavailability.
To address the foregoing issues, these lipophilic substances are usually administered in the form of liquid preparations dissolved in edible oils or formulated in oil-in-water emulsions or microemulsions. Even in these formulations, however, the oral bioavailability of many of them is still very low. Thus, even today, there remains an unresolved need to provide safe and useful formulations that provide enhanced oral bioavailability for such substances.
Coenzyme Q10 (CoQ10), chemically named as 2,3-dimethoxy-5-methyl-6-decaprenyl-1,4-benzoquinone and also known by the names Ubiquinone, and Vitamin Q, is classified as a fat-soluble quinone, a naturally occurring coenzyme. It has been identified as an essential component of the mitochondrial respiratory chain and, thus, a necessary part of a cell's energy production. More particularly, it constitutes a redox-link between flavoproteins and cytochromes and acts as an electron shuttle controlling the efficiency of oxidative phosphorylation. Without ubiquinone, cells cannot produce the energy necessary for all the body's many activities.
The name ubiquinone is derived from the word ubiquitous and, indeed, ubiquinone is a naturally occurring substance in almost every cell. Typically, the substance is found in small organelles called mitochondria, which act as the cell's energy factories. Mitochondria convert energy from nutritional substances to energy that is then used for all the body's activities.
CoQ10 has been previously identified as an antioxidant with potential use as a dietary supplement to protect against age-related degeneration and as an adjuvant vitamin to prevent or treat many disease states.
Supplementary Coenzyme Q10 has also reportedly shown beneficial influences in the following systems, conditions or diseases: periodontal disease, certain blood circulation diseases, impaired memory, fatigue, irregular heartbeat, high blood pressure, an immune system impairment, and the aging process. Moreover, Coenzyme Q10 has been reported to be capable of improving one's performance in sports.
Although known for many years to protect biological membranes against oxidation, CoQ10 has recaptured interest as a natural, powerful lipid-soluble antioxidant which acts as a membrane stabilizing agent. It, therefore, avoids lipid peroxidation and regulates lipid fluidity--probably by removing free radicals (Beyer R.E., The participation of coenzyme-Q in free radical production and anti-oxidation, Free Rad. Biol. Med., 8, 545-565, 1990). It is assumed that part of the substance's beneficial effect on heart disease and periodontal disease is due to its ability to neutralize free radicals in the affected tissue. Heart patients have been shown to have low levels of coenzyme Q10, and the liver's ability to produce coenzyme Q10 is debilitated as one becomes older.
The role of Coenzyme Q10 in the production of energy has also been demonstrated in the treatment of cardiomyopathy, a condition in which the actual muscle tissues of the heart are weakened, making it difficult for the heart to pump blood around the body effectively. Mortensen et al., have published results of long term coenzyme Q10 treatment for cardiomypathic patients (in Drugs under Experimental and Clinical Research, Vol 11, No. 8, pp. 581, 1985). Among 40 patients with severe heart failure, 69% showed improvements in their condition when treated with coenzyme Q10. Coenzyme Q10's beneficial affect on the heart's ability to pump is apparently due to its ability to increase the creation of the energy substance ATP in the heart. The strengthened heart is then better able to pump blood around the body.
The efficacy of coenzyme Q10 as an adjuvant therapy in heart diseases in a multicenter study has also been reported (Lampertico M., and Comis S., Italian multicenter study on the efficacy and safety of coenzyme Q10 as adjuvant therapy in heart failure, Clin. Investig., 71, S129-133, 1993). The most prevalent of all heart diseases is arteriosclerosis, a hardening of the heart's blood vessels and a condition often complicated by coronary thrombosis. Coenzyme Q10 has also been proposed to help fight this disease and strengthen the pumping action in cases where a lack of oxygen has debilitated the heart's muscle tissue.
Scientists have also investigated the effects of a dietary supplement of coenzyme Q10 on periodontitis. For example, in one study, the tissue samples of over 120 dental patients with periodontal disease were examined and were found to have a marked deficiency of CoQ10 (Wilkinson et al., Biomedical and Clinical Aspects of Coenzyme Q, pp 103-108, Elsevier/North Holland Biomedical Press, 1980). When the patients were treated with supplements containing CoQ10, the progress of the disease was not only stopped, but accelerated tissue healing was initiated as well. Such evidence appears to suggest that the spread of the disease can often be slowed down and, indeed, even stopped by coenzyme Q10. Coenzyme Q10 apparently facilitates the healing process by increasing the production of energy in the infected tissue. Coenzyme Q10 may also provide such benefits based on its antioxidant roperties which neutralize the harmful effects of free radicals.
Coenzyme Q10 has also been shown to protect cultured cerebellar neurons against age-related and excitotoxin-induced degeneration (Favit A., Nicoletti F., Scapagnini U., and Canonico P. L., Ubiquinone protects cultured neurons against spontaneous and excitotoxin-induced degeneration, J. Cerebral Blood Flow and Metab. 12, 638-645, 1992).
The recommended daily allowance for coenzyme Q10 has not been determined. Most experts agree, however, that the daily requirement lies somewhere between 30 and 60 milligrams. When treating illnesses, dosages of 100 to 300 milligrams are commonly used.
CoQ10 is a very lipophilic compound and practically insoluble in water due to its long side chain of 10 isoprenoid units. The oral bioavailability of CoQ10 is, therefore, generally very low and was found to be related to the dissolution rate of the formulation. The formulation of this substance in a suitable form affording convenient and efficient oral bioavailability is, therefore, a very desirable goal.
Emulsions and microemulsions have been shown to be advantageous vehicles for the oral delivery of lipophilic drugs, resulting in improved oral bioavailability of water-insoluble compounds (Tarr B. D. and Yalkowsky S. H., Enhanced intestinal absorption of cyclosporine in rats through the reduction of emulsion droplet size, Pharmac. Res. 6,40-43, 1989; Charman S. A., Charman W. N., Rogge M. C., Wilson T. D., Dutko F. J., and Pouton C. W., Self-dry lipid mixtures drug delivery systems: formulation and biopharmaceutic evaluation of an investigational lipophilic compound, Pharmac. Res. 9, 87-93, 1992).
Formulations of Coenzyme Q10 using lipids, in the form of emulsions, liposomes, microparticles and nanoparticles, have previously been disclosed. These known lipid formulations comprise particles dispersed in an aqueous medium, and are suitable for various routes of administration, including, primarily, intravenous administration, as disclosed in: WO 95/05164, which discloses microparticles and nanoparticles in aqueous suspension; U.S. Pat. No. 4,824,669, which discloses fatty emulsions; U.S. Pat. No. 4636381, which discloses liposomes; and U.S. Pat. No. 4,483,873, which discloses aqueous dispersions or solutions.
Other lipid formulations of Coenzyme Q10 have been disclosed for improved oral bioavailability, as in: WO 86/04503, which utilizes a high percentage of a synthetic surfactant agent together with a fat or with polyethylene glycol; JP 63188623, which discloses Coenzyme Q10 with middle chain fatty acid monoglycerine esters, and optional plant oil; and U.S. Pat. No. 4,684,520 which provides mixtures of Coenzyme Q10 with phospholipids.
Cannabinoids are one example of a family of lipophilic substances having very poor water solubility. Cannabinoids such as .DELTA..sup.1 -tetrahydrocannabinol (.DELTA..sup.1 -THC), .DELTA..sup.6 -tetrahydrocannabinol (.DELTA..sup.6 -THC), .DELTA..sup.9 -tetrahydrocannabinol (.DELTA..sup.9 -THC), cannabinol, cannabidiol, and their metabolites, are highly hydrophobic lipid soluble compounds and can be dissolved in aqueous solutions only in the range of a few micrograms/ml or less, depending upon conditions (Garret and Hunt, J. Pharm. Sci., 63:1056-1064, 1974).
In general, the systemic availability of cannabinoids after oral administration is low and mean estimates of the human bioavailability of tetrahydrocannabinol (THC) following oral ingestion range from 6 to 12% depending on the vehicle used. For example, the maximal plasma levels after oral dosing of 20 mg THC in a sesame oil formulation are around 10 ng/ml (Wall et al., Clin. Pharmacol. Ther. 34:352-363, 1983).
Dexanabinol, (+)-(3S,4S)-7-hydroxy-,.DELTA..sup.6 -tetra hydrocannabinol-1,1-dimetylheptyl,(also denoted HU-211), is disclosed in U.S. Pat. Nos. 4,876,276 and 5,521,215, as a synthetic non-psychoactive cannabinoid with novel neuroprotective activity in the multiple-action treatment of brain damage associated with stroke, head trauma, and cardiac arrest. The chemical structure of dexanabinol, (+)-(3S, 4S) -7-hydroxy-.DELTA..sup.6 -tetra hydrocannabinol-1,1-dimetylheptyl, is shown in Scheme 1. ##STR1## Dexanabinol is a very lipophilic compound which is practically insoluble in water (less than 50 .mu.g/ml) and, like other lipophilic drugs, exhibits poor oral bioavailability.